13-32316512-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The ENST00000530893(BRCA2):c.-314C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
ENST00000530893 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.31

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 13-32316512-C-T is Benign according to our data. Variant chr13-32316512-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184598.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 2 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000530893 link	c.-314C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000380152.8 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 2 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893 link	c.-314C>T		5_prime_UTR_variant	Exon 2 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.52C>T		non_coding_transcript_exon_variant	Exon 1 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R18C variant (also known as c.52C>T), located in coding exon 1 of the BRCA2 gene, results from a C to T substitution at nucleotide position 52. The arginine at codon 18 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in at least one individual from a cohort of breast, ovarian, and pancreatic cancer patients (Loizidou MA et al. Clin. Genet., 2017 Apr;91:611-615). This alteration was classified as likely benign by a multifactorial analysis that utilized data on co-occurrence, personal and family history, and tumor characteristics (Lee JS et al. J. Med. Genet., 2018 12;55:794-802). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Aug 28, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Jan 26, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition

Benign:1

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Sep 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27882536, 30415210, 31131967, 32444794) -

Hereditary breast ovarian cancer syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

0.046

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.14

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.58

MutPred

0.32

Loss of catalytic residue at R18 (P = 0.0172);Loss of catalytic residue at R18 (P = 0.0172);

MVP

0.87

MPC

0.14

ClinPred

0.95

GERP RS

2.3

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over